AB0121 MULTI-OMICS ANALYSIS REVEALS COX5A AS A BIOMARKER OF DISEASE ACTIVITY AND ORGAN DAMAGE OF LUPUS
Authors: M. Cai, Y. Qin, Z. Chen
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Systemic Lupus Erythematosus (SLE) is a heterogeneous systemic autoimmune disease with protean clinical manifestations<sup>[1]</sup>. Although the long-term outcome of patients with SLE has been greatly improved, increased organ damage is associated with poor prognosis in a number of patients. The type I interferon signature, a hallmark of SLE, is not an ideal treatment target or outcome predictor<sup>[2, 3]</sup>, suggesting other critical immunological pathways might contribute to disease pathogenesis. <h3>Objectives</h3> To explore key immunological pathways and gene markers in SLE more precisely, we performed a systematic analysis of transcriptional data from 27 immune cells in the blood and from single cells in the skin and kidney. <h3>Methods</h3> We included a large RNA-seq data from a total of 64 SLE and 62 control with 27 immune cells. Integrated analyses were conducted to find key pathways and driver genes in SLE pathogenesis. The expression of COX5A between SLE phenotypes was compared in two independent cohorts. Single-cell RNA sequencing(scRNA-seq) data from skin and kidney were used to further determine the association of COX5A expression with organ damage. <h3>Results</h3> We found that lymphocytes in SLE showed an overall active immuno-metabolic state when compared to healthy controls, and oxidative phosphorylation (OXPHOS) is the most significant metabolic pathway that differs between SLE and HC, especially for effector T cells. Besides, the OXPHOS enrichment score was significantly correlated with IFN response molecular signature across various T cell subtypes. Particularly, we identified an OXPHOS hub gene, COX5A, as a key driver in SLE T cells. COX5A expression was significantly higher in effector T cells than those in naïve T cells and showed associations with SLE clinical phenotypes including disease activity index, flare, and organ damage. Furthermore, we revealed that high expression of COX5A in T cells contributes to skin and kidney involvement of SLE through scRNA-seq analysis. <h3>Conclusion</h3> Our results identified OXPHOS signature is a prominent feature in SLE T cells. The key gene of OXPHOS, COX5A, showed associations with IFN response molecular signature, severity, skin, and kidney involvement of SLE, which supported that COX5A as a potential candidate biomarker of severity and organ damage of SLE. <h3>References</h3> [1]Takeshima, Y., et al., Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus. Ann Rheum Dis, 2022. <b>81</b>(6): p. 845-853. [2]Landolt-Marticorena, C., et al., Lack of association between the interferon-alpha signature and longitudinal changes in disease activity in systemic lupus erythematosus. Ann Rheum Dis, 2009. <b>68</b>(9): p. 1440-6. [3]Panwar, B., et al., Multi-cell type gene coexpression network analysis reveals coordinated interferon response and cross-cell type correlations in systemic lupus erythematosus. Genome Res, 2021. <b>31</b>(4): p. 659-676. <h3>Acknowledgements</h3> I have no acknowledgments to declare. <h3>Disclosure of Interests</h3> None Declared.